Hostname: page-component-745bb68f8f-mzp66 Total loading time: 0 Render date: 2025-02-07T06:14:50.131Z Has data issue: false hasContentIssue false
  • English
  • Français

Toxoplasma gondii: the changing paradigm of congenital toxoplasmosis

Published online by Cambridge University Press:  09 September 2011

D. S. LINDSAY  and
J. P. DUBEY
D. S. LINDSAY*
Affiliation:
Department of Biomedical Sciences and Pathobiology, Virginia – Maryland Regional College of Veterinary Medicine, Virginia Tech, 1410 Prices Fork Road, Blacksburg, VA 24061, USA
J. P. DUBEY
Affiliation:
United States Department of Agriculture, Animal Natural Resources Institute, Animal Parasitic Disease Laboratory, BARC-East, Building. 1001, Beltsville, MD 20705-2350, USA
*
*Corresponding author: Department of Biomedical Sciences and Pathobiology, Virginia Tech, 1410 Prices Fork Road, Blacksburg, VA 24061, USA. Tel: +1 540 321 6302. Fax: +1 540 231 3426. E-mail: lindsayd@vt.edu
Rights & Permissions [Opens in a new window]

Summary

Researchers have learned much concerning the population biology of Toxoplasma gondii over the past 2 decades. It is now apparent that many atypical genotypes exist besides the typical 3 genotypes (type I, type II and type III) first described from samples from Europe and the United States. These genotypes can differ in pathogenicity and transmissibility from the typical genotypes that have been used in the majority of scientific research over the past 70 years. These differences impact much of what we used to believe as facts about congenital toxoplasmosis (CT) and will be important in developing new recommendations for prevention of CT and the monitoring of women at risk for developing CT. The present review highlights new information on T. gondii genotypes and how this information will change the way we convey information about CT to pregnant women, physicians and students.

Keywords

Toxoplasma gondiicongenital toxoplasmosisgenotypespregnancy
Type
Review Article
Information
Parasitology , Volume 138 , Issue 14 , December 2011 , pp. 1829 - 1831
Copyright
Copyright © Cambridge University Press 2011

INTRODUCTION

Toxoplasma gondii is a zoonotic apicomplexan with a worldwide distribution (Dubey, Reference Dubey2010). It has a complex life cycle and causes a wide variety of symptoms in infected individuals. Infection in humans follows a course of active replication of the parasite and dissemination of the infection throughout the body followed by encystment in the brain, retina, and other organs as latent tissue cysts. Congenital toxoplasmosis (CT) has long been recognized because of the devastating results it can have on the infected fetus including miscarriage, mental retardation, visual, and hearing problems (Weiss and Dubey, Reference Weiss and Dubey2009). Until recently, it was believed that transmission of T. gondii to the fetus occurred predominantly in women who acquired their primary infection during gestation (Remington et al. Reference Remington, McLeod, Thuilliez, Desmonts, Remington, Klein, Wilson and Baker2006). Only in rare cases was congenital transmission of T. gondii found to occur in chronically infected women whose infection became reactivated because of immunosuppression from AIDS or treatment with corticosteroids for underlying disease (Remington et al. Reference Remington, McLeod, Thuilliez, Desmonts, Remington, Klein, Wilson and Baker2006).

Old beliefs

The old thinking on CT was that women of childbearing age that had antibodies to T. gondii were immune and would not transmit the infection to their fetus. Women that did not have antibodies indicative of exposure to T. gondii were therefore considered to be at risk of acquiring the infection during pregnancy and transmitting it to their offspring. The risk of a fetus becoming infected with T. gondii and the severity of outcome of infection was believed to be related to the trimester in which the mother was exposed to T. gondii (Dunn et al. Reference Dunn, Wallon, Peyron, Petersen, Peckham and Gilbert1999). Exposure early in pregnancy (1st trimester) results in fewer fetal infections but the severity of disease is more pronounced than if infection occurs later in pregnancy (3rd trimester) when more transmission is likely to occur, but the disease is usually less severe. Most pregnant women do not experience symptoms of infection (Remington et al. Reference Remington, McLeod, Thuilliez, Desmonts, Remington, Klein, Wilson and Baker2006) and have no reason to seek medical attention so infection goes undiagnosed. Exposure to raw or undercooked meat containing viable tissue cysts, produce or water contaminated with oocysts, and exposure to kittens (source of oocysts) are risk factors for T. gondii infection (Dubey, Reference Dubey2010).

These beliefs were the foundation for the following recommendations for detection of CT in pregnant women in countries where CT is a recognized problem. Prevention of CT and its detection became national policy in France in the late 1970s and requires: (i) the detection and follow-up of T. gondii serologically negative (non-immunized) women as soon as possible during pregnancy; (ii) appropriate counselling and education aiming at limiting the risks of maternal exposure to both tissue cysts and oocysts); (iii) the detection and treatment of toxoplasmosis as early as possible aiming to prevent or limit transmission to the fetus and the severity of CT; (iv) post-natal examination for signs of CT using monthly ultrasound examinations in cases of maternal seroconversion during surveillance; (v) combined sulfadiazine-pyrimethamine treatment during pregnancy if CT is proven; and (vi) clinical, radiological and serological surveillance of neonates and infants at risk (Sterkers et al. Reference Sterkers, Varlet-Marie, Marty and Bastien2010; Villena et al. Reference Villena, Ancelle, Delmas, Garcia, Brezin, Thulliez, Wallon, King and Goulet2010).

Toxoplasma gondii and CT in humans: a changing paradigm

A new concept of congenital human toxoplasmosis has been evolving over the last few decades and can be attributed to the findings of the different genotypes of T. gondii that are present in various areas of the world (Howe and Sibley, Reference Howe and Sibley1995; Su et al. 2010). There are 3 major genotypes (Howe and Sibley, Reference Howe and Sibley1995) that account for 95% of the isolates in North America and Europe and the remaining 5% of isolates are termed atypical (or exotic) because they do not fall into the 3 major clonal lineages but this concept is changing and greater genetic diversity is now realized (Khan et al. Reference Khan, Dubey, Su, Ajioka, Rosenthal and Sibley2011). The T. gondii genotypes differ in their pathogenicity for mice, and prevalence in humans. The low linkage disequilibrium among genetic loci of these atypical isolates suggests that they have undergone frequent sexual recombination (Su et al. 2010; Khan et al. 2011).

The Type II genotype of T. gondii is responsible for most cases of CT in Europe and the United States. CT in T. gondii seropositive mothers (immune) from Europe indicates that atypical genotypes can overcome the acquired resistance from the original infecting genotype (Elbez-Rubinstein et al. Reference Elbez-Rubinstein, Ajzenberg, Darde, Cohen, Dumètre, Yera, Gondon, Janaud and Thulliez2009). A recent study demonstrated that severe CT could occur in children of non-immune mothers infected in the 3rd trimester (Delhaes et al. Reference Delhaes, Ajzenberg, Sicot, Bourgeot, Dardé, Dei-Cas and Houfflin-Debarge2010), which is a rare occurrence in CT caused by the typical genotypes.

Congenital toxoplasmosis in humans occurs in 4 major ways

It is now recognized that CT can occur by 4 different ways. The first way that transmission of T. gondii to the fetus can occur is in women who acquire their primary infection during gestation (Remington et al. Reference Remington, McLeod, Thuilliez, Desmonts, Remington, Klein, Wilson and Baker2006). Most of our knowledge is based on women from Europe that are most frequently infected with typical genotypes (usually Type II). The relationship between stage of pregnancy when infection occurs and the potential for infection and disease in the offspring are based on medical information from these women. The general thinking is that as pregnancy progresses, the chance of fetal infection increases but the chance that severe disease developing in the fetus decreases (Remington et al. Reference Remington, McLeod, Thuilliez, Desmonts, Remington, Klein, Wilson and Baker2006; Dubey, Reference Dubey2010). We know less of the primary infection with atypical T. gondii genotypes during pregnancy and the predicted outcome of CT in the infected infants (Ajzenberg et al. Reference Ajzenberg, Cogné, Paris, Bessières, Thulliez, Filisetti, Pelloux, Marty and Dardé2002; Cneude et al. Reference Cneude, Deliege, Barbier, Durand-Joly, Bourlet, Sonna, El Kohen, Locquet, Vittu and Decoster2007; Demar et al. Reference Demar, Ajzenberg, Maubon, Djossou, Panchoe, Punwasi, Valery, Peneau, Daigre, Aznar, Cottrelle, Terzan, Dardé and Carme2007; Delhaes et al. Reference Delhaes, Ajzenberg, Sicot, Bourgeot, Dardé, Dei-Cas and Houfflin-Debarge2010). Congenital toxoplasmosis caused by atypical genotypes is more severe than CT caused by typical genotypes (Delhaes et al. Reference Delhaes, Ajzenberg, Sicot, Bourgeot, Dardé, Dei-Cas and Houfflin-Debarge2010). Six of 8 atypical CT cases were severe and resulted in medical termination of pregnancy or death a few days after birth. Three of the 8 cases were acquired during the 3rd trimester (Delhaes et al. Reference Delhaes, Ajzenberg, Sicot, Bourgeot, Dardé, Dei-Cas and Houfflin-Debarge2010). It currently appears that, unlike the typical genotypes, infections with atypical genotypes in the 3rd trimester can result in severe CT. Atypical genotypes are associated with more severe ocular disease in children with CT from Brazil than Europe (Gilbert et al. Reference Gilbert, Freeman, Lago, Bahia-Oliveira, Tan, Wallon, Buffolano, Stanford and Petersen2008).

A second way is transmission by immunocompetent women infected shortly before pregnancy. This is associated with acquisition of infection a few months before pregnancy and is thought to be due to persistent parasitaemia that continues after the pregnancy is established (Marty et al. Reference Marty, Le Fichoux, Deville and Forest1991; Pons et al. Reference Pons, Sigrand, Grangeot-Keros, Frydman, Frydman and Thulliez1995; Vogel et al. Reference Vogel, Kirisits, Michael, Bach, Hostetter, Boyer, Simpson, Holfels, Hopkins, Mack, Mets, Swisher, Patel, Roizen, Stein, Stein, Withers, Mui, Egwuagu, Remington, Dorfman and McLeod1996; Dollfus et al. Reference Dollfus, Dureau, Hennequin, Uteza, Bron and Dufier1998; Villena et al. Reference Villena, Chemla, Quereux, Dupouy, Leroux, Foudrinier and Pinon1998; Boumahni et al. Reference Boumahni, Randrianivo, Flodrops, Kauffmann, Sauve, Chauvet, Renouil and Fourmaintraux2004). Little is known of differences in duration of parasitaemia between typical and atypical genotypes and what role it has in causing CT.

A third way of transmission is by true reactivation of CT in HIV-infected mothers (Desmonts et al. Reference Desmonts, Couvreur and Thulliez1990; Marty et al. Reference Marty, Bongain, Rahal, Thulliez, Wasfi, Lambert, Le Fichoux and Gillet1994, Reference Marty, Bongain, Loiseau, Benoit, Chevallier, Gillet and Le Fichoux2002; Bachmeyer et al. Reference Bachmeyer, Mouchnino, Thulliez and Blum2006; Azevedo et al. Reference Azevedo, Setúbal, Lopes, Camacho and Oliveira2010) or mothers that have immunologically altered immune function due to systemic lupus erythematosus or malignancies of their haematological systems (Desmonts et al. Reference Desmonts, Couvreur and Thulliez1990). The importance of T. gondii genotype and the likelihood that reactivation will occur in immunosuppressed pregnant women is currently unknown.

The fourth way of transmission is in a mother immune to a typical genotype challenged by an atypical genotype during pregnancy and subsequently transmitting the atypical genotype to their offspring (Fortier et al. Reference Fortier, Aissi, Ajana, Dieusart, Denis, Martin de Lassalle, Lecomte-Houcke and Vinatier1991; Gavinet et al. Reference Gavinet, Robert, Firtion, Delouvrier, Hennequin, Maurin, Tourte-Schaefer and Dupouy-Camet1997; Hennequin et al. Reference Hennequin, Dureau, N'Guyen, Thulliez, Gagelin and Dufier1997; Kodjikian et al. Reference Kodjikian, Hoigne, Adam, Jacquier, Aebi-Ochsner, Aebi and Garweg2004; Lebas et al. Reference Lebas, Ducrocq., Mucignat, Paris, Mégier, Baudon and Gold2004; Elbez-Rubinstein et al. Reference Elbez-Rubinstein, Ajzenberg, Darde, Cohen, Dumètre, Yera, Gondon, Janaud and Thulliez2009). These cases are in mothers that live in a country where type II genotypes of T. gondii predominate and exposure to T. gondii is thought to be from atypical genotypes acquired by visiting or consumption of products from a country that has predominantly atypical genotypes. The ability of a previous infection with an atypical genotype of T. gondii and the protection it induces to challenge with typical or other atypical genotypes of T. gondii is not currently known. This fourth mode of transmission is contrary to the widely held belief that if a woman is infected with T. gondii prior to pregnancy then she is immune to re-infection and will not transmit the infection to her developing child. This is the basis for maternal screening of pregnant women for T. gondii in countries where it is practiced.

New challenge

Serological tests currently available for clinical use cannot differentiate between typical and atypical genotypes of T. gondii. Maternal testing methods and recommendations for T. gondii need to be re-evaluated in light of recent clinical evidence to include the potential for exposure to atypical genotypes during pregnancy. Educators need to revise the information they teach on CT to medical, veterinary, graduate and undergraduate students.

References

REFERENCES

Ajzenberg, D., Cogné, N., Paris, L., Bessières, M. H., Thulliez, P., Filisetti, D., Pelloux, H., Marty, P. and Dardé, M. L. (2002). Genotype of 86 Toxoplasma gondii isolates associated with human congenital toxoplasmosis, and correlation with clinical findings. Journal of Infectious Diseases 186, 684–689.CrossRefGoogle ScholarPubMed
Azevedo, K. M., Setúbal, S., Lopes, V. G., Camacho, L. A. and Oliveira, S. A. (2010). Congenital toxoplasmosis transmitted by human immunodeficiency-virus infected women. Brazilian Journal of Infectious Disease 14, 186–189.CrossRefGoogle ScholarPubMed
Bachmeyer, C., Mouchnino, G., Thulliez, P. and Blum, L. (2006). Congenital toxoplasmosis from an HIV-infected woman as a result of reactivation. Journal of Infection 52, e55–57.CrossRefGoogle ScholarPubMed
Boumahni, B., Randrianivo, H., Flodrops, H., Kauffmann, E., Sauve, F., Chauvet, O., Renouil, M. and Fourmaintraux, A. (2004). Maternal toxoplasmosis before conception and chorioretinitis in twin sisters. Journal of Gynecology Obstetrics and Biology of Reproduction (Paris) 33, 248–250.CrossRefGoogle ScholarPubMed
Cneude, F., Deliege, R., Barbier, C., Durand-Joly, I., Bourlet, A., Sonna, M., El Kohen, R., Locquet, A, Vittu, G. and Decoster, A. (2003). Septic shock due to congenital disseminated toxoplasmosis? Archives of Pediatrics 10, 326–328.CrossRefGoogle ScholarPubMed
Delhaes, L., Ajzenberg, D., Sicot, B., Bourgeot, P., Dardé, M. L., Dei-Cas, E. and Houfflin-Debarge, V. (2010). Severe congenital toxoplasmosis due to a Toxoplasma gondii strain with an atypical genotype: case report and review. Prenatal Diagnosis 30, 902–905.CrossRefGoogle ScholarPubMed
Demar, M., Ajzenberg, D., Maubon, D., Djossou, F., Panchoe, D., Punwasi, W., Valery, N., Peneau, C., Daigre, J. L., Aznar, C., Cottrelle, B., Terzan, L., Dardé, M. L. and Carme, B. (2007). Fatal outbreak of human toxoplasmosis along the Maroni River: epidemiological, clinical, and parasitological aspects. Clinical Infectious Diseases 45, e88–e95.CrossRefGoogle ScholarPubMed
Desmonts, G., Couvreur, J. and Thulliez, P. (1990). Congenital toxoplasmosis: 5 cases of mother-to-child transmission of pre-pregnancy infection. La Presse Médicale 19, 1445–1449.Google ScholarPubMed
Dollfus, H., Dureau, P., Hennequin, C., Uteza, Y., Bron, A. and Dufier, J. L. (1998). Congenital Toxoplasma chorioretinitis transmitted by preconceptionally immune women. British Journal of Ophthalmology 82, 1444–1445.CrossRefGoogle ScholarPubMed
Dubey, J. P. (2010). Toxoplasmosis of Animals and Humans, 2nd Edn. CRC Press, Boca Raton, FL, USA.Google Scholar
Dunn, D., Wallon, M., Peyron, F., Petersen, E., Peckham, C. and Gilbert, R. (1999). Mother-to-child transmission of toxoplasmosis: risk estimates for clinical counseling. Lancet 353, 1829–1833.CrossRefGoogle Scholar
Elbez-Rubinstein, A., Ajzenberg, D., Darde, M. L., Cohen, R., Dumètre, A., Yera, H., Gondon, E., Janaud, J. C. and Thulliez, P. (2009). Congenital toxoplasmosis and reinfection during pregnancy: case report, strain characterization, experimental model of reinfection, and review. Journal of Infectious Diseases 199, 280–285.CrossRefGoogle ScholarPubMed
Fortier, B., Aissi, E., Ajana, F., Dieusart, P., Denis, P., Martin de Lassalle, E., Lecomte-Houcke, M. and Vinatier, D. (1991). Spontaneous abortion and reinfection by Toxoplasma gondii. Lancet 338, 444.CrossRefGoogle ScholarPubMed
Gavinet, M. F., Robert, F., Firtion, G., Delouvrier, E., Hennequin, C., Maurin, J. R., Tourte-Schaefer, C. and Dupouy-Camet, J. (1997). Congenital toxoplasmosis due to maternal reinfection during pregnancy. Journal of Clinical Microbiology 35, 1276–1277.CrossRefGoogle ScholarPubMed
Gilbert, R. E., Freeman, K., Lago, E. G., Bahia-Oliveira, L. M., Tan, H. K., Wallon, M., Buffolano, W., Stanford, M. R., Petersen, E. and European Multicentre Study on Congenital Toxoplasmosis (EMSCOT) (2008). Ocular sequelae of congenital toxoplasmosis in Brazil compared with Europe. PLoS Neglected Tropical Diseases 2, e277.CrossRefGoogle ScholarPubMed
Hennequin, C., Dureau, P., N'Guyen, L., Thulliez, P., Gagelin, B. and Dufier, J. L. (1997). Congenital toxoplasmosis acquired from an immune woman. Pediatric Infectious Disease Journal 16, 75–77.CrossRefGoogle ScholarPubMed
Howe, D. K. and Sibley, L. D. (1995). Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease. Journal of Infections Diseases 172, 1561–1566.CrossRefGoogle ScholarPubMed
Khan, A., Dubey, J. P., Su, C., Ajioka, J. W., Rosenthal, B. M. and Sibley, L. D. (2011). Genetic analyses of a typical Toxoplasma gondii strains reveal a fourth clonal lineage in North America. International Journal for Parasitology 41, 645–655.CrossRefGoogle Scholar
Kodjikian, L., Hoigne, I., Adam, O., Jacquier, P., Aebi-Ochsner, C., Aebi, C. and Garweg, J. (2004). Vertical transmission of toxoplasmosis from a chronically infected immunocompetent woman. Pediatric Infectious Disease Journal 23, 272–274.CrossRefGoogle ScholarPubMed
Lebas, F., Ducrocq., S, Mucignat, V., Paris, L., Mégier, P., Baudon, J. J. and Gold, F. (2004). Congenital toxoplasmosis: a new case of infection during pregnancy in a previously immunized and immunocompetent woman. Archives de Pédiatrie 11, 926–928.CrossRefGoogle Scholar
Marty, P., Bongain, A., Loiseau, S., Benoit, B., Chevallier, A., Gillet, J. Y. and Le Fichoux, Y. (2002). Lethal congenital toxoplasmosis resulting from reactivation of toxoplasmosis in a pregnant HIV-positive patient. La Presse Médicale 31, 1558.Google Scholar
Marty, P., Bongain, A., Rahal, A., Thulliez, P., Wasfi, D., Lambert, J. C., Le Fichoux, Y. and Gillet, J. Y. (1994). Prenatal diagnosis of severe fetal toxoplasmosis as a result of toxoplasmic reactivation in an HIV-1 seropositive woman. Prenatal Diagnosis 14, 414–415.CrossRefGoogle Scholar
Marty, P., Le Fichoux, Y., Deville, A. and Forest, H. (1991). Congenital toxoplasmosis and preconceptional maternal ganglionic toxoplasmosis [in French]. La Presse Médicale 20, 387.Google ScholarPubMed
Pons, J. C., Sigrand, C., Grangeot-Keros, L., Frydman, R., Frydman, R. and Thulliez, P. (1995). Congenital toxoplasmosis: transmission to the fetus of a pre-pregnancy maternal infection. La Presse Médicale 24, 179–182.Google Scholar
Remington, J. S., McLeod, R., Thuilliez, P. and Desmonts, G. (2006). Toxoplasmosis. In Infectious Diseases of the Fetus and Newborn Infant 6th Edn (ed. Remington, J. S., Klein, J. O., Wilson, C. B. and Baker, C.), pp. 947–1091. Elsevier Saunders, Philadelphia, PA, USA.CrossRefGoogle Scholar
Sterkers, Y., Varlet-Marie, E., Marty, P., Bastien, P. and the ANOFEL Toxoplasma-PCR Quality Control Group. (2010). Diversity and evolution of methods and practices for the molecular diagnosis of congenital toxoplasmosis in France: a 4-year survey. Clinical Microbiology and Infection 16, 1594–1602.CrossRefGoogle Scholar
Su, C., Shwab, E. K., Zhou, P., Zhu, X. Q. and Dubey, J. P. (2010). Moving towards an integrated approach to molecular detection and identification of Toxoplasma gondii. Parasitology 137, 1–11.CrossRefGoogle ScholarPubMed
Villena, I., Ancelle, T., Delmas, C., Garcia, P., Brezin, A. P., Thulliez, P., Wallon, M., King, L., Goulet, V. and the Toxosurv network and National Reference Centre for Toxoplasmosis. (2010). Congenital toxoplasmosis in France in 2007: first results from a national surveillance system. European Surveillance 15, pii: 19600.Google ScholarPubMed
Villena, I., Chemla, C., Quereux, C., Dupouy, D., Leroux, B., Foudrinier, F. and Pinon, J. M. (1998). Prenatal diagnosis of congenital toxoplasmosis transmitted by an immunocompetent woman infected before conception. Reims Toxoplasmosis Group. Prenatal Diagnosis 18, 1079–1081.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Vogel, N., Kirisits, M., Michael, E., Bach, H., Hostetter, M., Boyer, K., Simpson, R., Holfels, E., Hopkins, J., Mack, D., Mets, M. B., Swisher, C. N., Patel, D., Roizen, N., Stein, L., Stein, M., Withers, S., Mui, E., Egwuagu, C., Remington, J., Dorfman, R. and McLeod, R. (1996). Congenital toxoplasmosis transmitted from an immunologically competent mother infected before conception. Clinical Infectious Diseases 23, 1055–1060.CrossRefGoogle ScholarPubMed
Weiss, L. M. and Dubey, J. P. (2009). Toxoplasmosis: A history of clinical observations. International Journal for Parasitology 39, 895–901.CrossRefGoogle ScholarPubMed